Devices that deliver drugs through the skin for absorption into the body have been known for some time. For example, U.S. Pat. No. 3,249,109 describes a two-layer topical dressing that consists of an adhesive base made of drug-containing hydrated gelatin with a fabric backing layer. This type of device could be considered a "skin-controlled" device because the system delivers an excess of drug to the skin and the rate of absorption is controlled by the permeability of the skin at the application site which can vary over relatively wide ranges from site-to-site and individual-to-individual. In order to deliver transdermal drugs having a relatively narrow therapeutic range, and for which such wide variations could not be tolerated, "system-controlled" delivery devices were developed which deliver drugs transdermally at rates which are controlled primarily by the delivery device to reduce or eliminate the variations in drug input rate associated with variations in skin permeability. For example, U.S. Pat. No. 3,598,122 describes a multilayer adhesive bandage formed of a backing layer, a drug reservoir layer and a contact adhesive layer, and includes means for metering the rate at which the drug is released to the skin. Other representative system controlled transdermal drug delivery devices are described in U.S. Pat. Nos. 3,797,494 and 4,379,454, the latter of which teaches controlling the rate at which a drug is absorbed through the skin by controlling the rate at which a permeation enhancer for the drug is delivered to the skin. (All of the aforementioned U.S. patents are incorporated herein by reference.) In addition, Black, "Transdermal Drug Delivery Systems", U.S. Pharmacist, November 1982, pp. 49-78, provides additional background information regarding commercially available transdermal drug delivery systems and a reasonably complete summary of the factors involved in percutaneous absorption of drugs may be found in Arita, et al, "Studies on Percutaneous Absorption of Drugs", Chem. Phar. Bull., Vol. 18, 1970, pp. 1045-1049; Idson, "Percutaneous Absorption", J. Phar. Sci., Vol. 64, No. 6, pp. 910-922; and Cooney, Advances in Biomedical Engineering, Part 1, Chapter 6, "Drug Permeation Through Skin: Controlled Delivery for Topical of Systemic Therapy", Marcel Dekker, Inc., New York and Basel, 1980 pp. 305-318.
Although the transdermal drug delivery route is rapidly becoming a preferred delivery route for a wide variety of drugs, transdermal delivery is not without its problems. A large number of drugs are oil-insoluble and in aqueous solutions exist, depending on pH, either as the unionized acid or base or in the ionized salt form. The unionized forms of most drugs are generally more permeable through the skin than the ionized drug making it easier to achieve, either with or without permeation enhancers, blood levels which are capable of producing the desired therapeutic effects. (See R. J. Scheuplein, et al., "Permeability of the Skin", Physiological Reviews, Vol. 51, No. 4, October 1972, pp. 702-747, particularly 729-735). Unfortunately, the pH of aqueous solutions of a free base or acid is usually below 3 for the acid or above 10 for the base, and transdermal delivery at these pH's may cause discomfort and/or irritation to the skin of the recipients. Adjusting the pH of solutions of these drugs to a more physiologically acceptable level (e.g., 5-8) results in a substantial proportion of the drug being converted to the nonpermeable, ionized form. As a result, prior to our invention we are unaware of any transdermal drug delivery system which is capable of delivering the ionized form of highly ionized, fat insoluble drugs at rates adequate to produce desired therapeutic effects.
It is accordingly an object of this invention to provide a medical device for transdermal drug delivery adapted to deliver the ionized form of a highly ionized, fat insoluble drug.
It is another object of this invention to provide a transdermal drug delivery device capable of delivering a highly ionized, fat insoluble drug from an aqueous reservoir.
It is another object of this invention to provide a transdermal drug delivery device in which a highly ionized, fat insoluble drug is delivered at a substantially physiological pH.
It is another object of this invention to provide a transdermal drug delivery device capable of delivering the ionized form of a fat insoluble drug at a substantially constant rate.
It is another object of this invention to provide reservoir compositions useful in the aforementioned drug delivery devices.